CN116178373B - 非甾体抗炎药和gs-441524的二联体化合物及其制备方法与用途 - Google Patents
非甾体抗炎药和gs-441524的二联体化合物及其制备方法与用途 Download PDFInfo
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明属于抗冠状病毒感染药物领域，具公开了非甾体抗炎药和GS‑441524的二联体化合物，如I所示结构NSAID指非甾体抗炎药酯化后的残基。本发明还提供上述二联体化合物的合成路线，本发明的化合物可以提高GS‑441524的细胞膜渗透性、改善药代动力学性质，并提高其抗冠状病毒感染的体内疗效。
Description
技术领域
本发明属于抗冠状病毒感染药物领域，具体涉及非甾体抗炎药和GS-441524的二联体化合物及其制备方法与用途。
背景技术
冠状病毒是一种阳性、单链、包膜RNA病毒，可感染包括人类和多种动物在内的广泛宿主，并有跨越物种屏障的趋势。
核苷及其类似物是作为单一化合物以及鸡尾疗法的一线治疗病毒性感染疾病的药物。瑞德西韦是一种经静脉给药的磷酰亚胺前药，是第一个获批用于治疗SARS-CoV-2感染的药物。非住院高危患者早期使用瑞德西韦可降低87％的住院或死亡风险。然而，作为一种血浆半衰期短(T1/2为1小时)的强制性静脉注射药物，给药物的临床应用带来了极大的限制。GS-441524是瑞德西韦的前体药物，研究者发现，亲本核苷GS-441524在体外对抗SARS-CoV-2的效力比瑞德西韦更强，腹腔注射GS-4415124在SARS-CoV-2感染的Ad5-hACE2小鼠中显示出强大的抗病毒效力。但是，GS-4415204在啮齿动物和非人灵长类动物中表现出较差的口服生物利用度。因此，需要对GS-4415204进行结构改进，以改善其生物利用度，提升抗病毒能力。
SARS-CoV-2通过结合其启动子导致环氧合酶-2(COX-2)过度表达，并促进前列腺素(PG)的产生，导致疼痛和炎症。COX-2是严重性炎症反应的重要组成部分，为过度炎症和细胞因子风暴关键酶。
非甾体抗炎药(NSAIDs)是一类具有解热镇痛效果的药物，在施用较高剂量时也具有消炎作用。大多数的非甾体抗炎药抑制了环氧合酶-1(COX-1)以及环氧合酶-2(COX-2)，进而减少前列腺素和血栓素的合成。一般认为，非甾体抗炎药因为抑制环氧合酶-2会有解热镇痛、抗炎的效果。部分非甾体抗炎药，如阿司匹林，也同时抑制了环氧合酶-1(COX-1)，因而容易导致肠胃道出血和溃疡。
发明内容
本发明为了改善GS-441524化合物的药代动力学性质，开发一种具有广谱抗冠状病毒活性口服药物，增加其抗病毒活性和体内效果，运用孪药原理得到一系列新型结构的具有口服抗病毒活性的GS-441524和非甾体抗炎药的二联体。
为此，本发明采用以下技术方案：
一种如式I所示结构的非甾体抗炎药和GS-441524的二联体化合物或其药学上可接受的盐或前药：
NSAID指非甾体抗炎药酯化后的残基。
酯化后的残基是指NSAID的羧基与GS-441524的5’-羟基形成酯键之后，残余的羧酸片段，如布洛芬酯化后的残基为
进一步地，所述非甾体抗炎药为非诺洛芬、萘普生、酮洛芬、布洛芬、双氯芬酸、吲哚美辛或阿司匹林。
进一步地，二联体化合物或其药学上可接受的盐或前药选自以下化合物：
化合物ATV038：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)-2-(3-苯氧基苯基)丙酸甲酯
化合物ATV039：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲基(S)-2-(6-甲氧基萘-2-)丙酸甲酯
化合物ATV040 ：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)-2-(3-苯甲酰基苯基)丙酸甲酯
化合物ATV041：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)-2-(4-异丁基苯基)丙酸甲酯
化合物ATV042：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲基-2-(2-((2,6-二氯苯基)氨基)苯基)乙酸酯
化合物ATV043：((2R，3S，4R，5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲基-2-(1-(4-氯苯甲酰)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酸甲酯
进一步地，二联体化合物或其药学上可接受的盐或前药，所述式I所示结构包括式I所示结构的外消旋体、立体异构体、互变异构体、包合物、多晶型物、假多晶型物、无定形形式、水合物或溶剂化物。
除非另外指明，本发明的化合物还包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如，具有式I所示结构，用氘或氚替换氢，或者用13C或14C富集的碳原子替换碳原子，或15N富集的氮原子替换氮原子的化合物属于本发明的范畴内。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
“药学上可接受的盐或前药”是指任何药学上所接受的盐，或经施用于接受者后能够提供(直接或间接)本文所述化合物的其他化合物。
本发明所使用的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为本领域技术人员所熟知的，如文献：S.M.Berge et al.，describe pharmaceutically acceptable salts in detail in J.PharmaceuticalSciences，1977，66：1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，无机酸盐，如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐；有机酸盐，如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括，己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐等。通过与适当的碱反应得到的盐包括碱金属，碱土金属，铵盐。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，磺酸化物和芳香磺酸化物。
氮原子或氨基的生理上可接受的盐包括：(a)与无机酸形成的酸加成盐，所述无机酸例如，氢氯酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等；(b)与有机酸形成的盐，所述有机酸例如，醋酸、草酸、酒石酸、琥珀酸、马来酸、延胡索酸、葡糖酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、羟乙磺酸、乳糖酸、鞣酸、棕榈酸、海藻酸、聚谷氨酸、萘磺酸、甲磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、聚半乳糖醛酸、丙二酸、磺基水杨酸、羟乙酸、2-羟基-3-萘甲酸盐、双羟萘酸盐、水杨酸、硬脂酸、苯二甲酸、苦杏仁酸、乳酸、乙磺酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸、亮氨酸等；和(c)与元素阴离子形成的盐，所述元素阴离子例如，氯、溴和碘。
羟基化合物的生理上可接受的盐包括所述化合物的阴离子与诸如Na+和NR4 +的适当阳离子的组合。
可接受的酯包括所述化合物的羟基与羧酸或无机含氧酸发生酯化反应生成的产物。
式I化合物前药的任何化合物属于本发明的范围内，术语“前药”以其最广泛的意义使用并且包括在体内转化为本发明化合物的那些衍生物。这些衍生物对于本领域技术人员是显而易见的，前体药物设计时，最常见的形式是对含羧基、羟基、氨基的药物进行结构修饰，制成酯、羧酸酯、氨基酸酯、酰胺、磷酸酯等类型的前药，另外还可制成偶氮型前药、一氧化氮型前药及开环、闭环等新型结构的前体药物。
优选的前药是相对于母体物质，当将这些化合物使用于患者时提高本发明化合物的生物利用度(例如通过使得口服给药的化合物更容易被吸收到血液中)或增强母体化合物向生物区室(脑或淋巴系统)的传递的那些。
本发明的化合物可以是作为有利于化合物或作为溶剂化物的晶体形式，这两种形式都包括在本发明的范围内。溶剂化的方法是本领域公知的。适当的溶剂化物是药用溶剂化物。
包合物是指由两个化合物结合而成的一个复合物，其中一个化合物(主)形成一个空腔，而空腔里面存在另一个化合物(客)。包合物的定义很明确，由化合物(主)晶体内提供一个由中间分子组成且符合化合物(客)的通道。若是化合物(主)晶体的内空间全面地封锁住时，使化合物(客)看起来就好像被关在笼子内的样子，也就是所谓的络合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。
术语“水合物”是指溶剂分子是水所形成的缔合物。
式I化合物可以以多晶型物或假多晶型物存在。本文使用的晶体多晶型现象是指晶体化合物以不同晶体结构存在的能力。晶体多晶型现象可以源自晶体堆积中的差异(堆积多晶型现象)或相同分子的不同构象异构体之间的堆积差异(构象多晶型现象)。本文使用的晶体假多晶型现象是指化合物的水合物或溶剂化物以不同晶体结构存在的能力。本发明的假多晶型物可以由于晶体堆积中的差异(堆积假多晶型现象)或由于相同分子的不同构象异构体之间的堆积差异(构象假多晶型现象)而存在。本发明式I化合物或其药学上可接受的盐或前药包括它们的所有多晶型物和假多晶型物。
式I化合物还可以作为无定形固体存在。本文使用的无定形固体是这样的固体，其中所述固体中的原子的位置不存在长程有序。当晶体大小是2纳米或更小时，该定义也适用。可以使用包括溶剂在内的添加剂，建立本发明的无定形形式。本发明式I化合物或其药学上可接受的盐或前药包括它们的所有无定形形式。
术语“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。大多数互变异构都涉及氢原子或质子的转移，以及单键向双键的转变。互变异构体在平衡中的分布与具体的因素有关，包括温度、溶剂和pH值等。例如，质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2，4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等。
对映异构体是指一个化合物的两个不能重叠但互成镜像关系的异构体。对于给定的化学构造来说，除了它们是互为镜像之外，这些立体异构体是相同的。一种特殊的立体异构体也被称为对映异构体，并且这类异构体的混合物常被称作对映异构体混合物。
术语外消旋体是指两种对映异构体物质的等摩尔混合物，缺乏旋光性。对映异构体的50：50混合物被称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，它可以产生。
非对映异构体是指有两个或多个手性中心并且其分子不互为镜像的立体异构体，包括顺反异构体、构象异构体、内消旋化合物和具有非对映关系的光学异构体。狭义地讲，非对映异构体仅包含具有一个或多个手性中心但不互为镜像关系的化合物。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本文所述化合物的体内代谢产物(不包括GS-441524)也落在本发明的范围之内，其程度是，这样的产物相对于现有技术是新颖的且非显而易见的。这些产物可产生自，例如，施用的化合物的氧化、还原、水解、酰胺化、酯化等，主要是由于酶过程。因此，本发明包括通过以下方法生产的新颖的且非显而易见的化合物，该方法包括，使本发明化合物与哺乳动物接触足够产生其代谢产物的一段时间。此类产物典型如下鉴定：制备放射标记(例如14C或3H)的本发明化合物，将它以可检测的剂量(例如大于约0.5mg/kg)肠胃外地施用给动物，例如大鼠、小鼠、豚鼠、猴或人，允许发生代谢的足够时间(典型地，约30秒到30小时)，并从尿、血或其它生物样品中分离它的转化产物。由于它们被标记，这些产物很容易分离(其它是使用能结合残留在代谢产物中的表位的抗体来分离)。代谢产物的结构以常规方式测定，例如用MS或NMR分析。一般而言，代谢产物的分析以与本领域技术人员公知的常规药物代谢研究相同的方法进行。转化产物，条件是它们不以其它方式在体内被发现，即使它们自身不具有新冠病毒聚合酶抑制活性，也可用于本发明化合物的治疗给药的诊断测定。
二联体化合物或其药学上可接受的盐或前药的制备方法，包括以下步骤：
使GS-441524和2,2-二甲氧基丙烷反应得到中间体1；
使中间体1与非甾体抗炎药反应得到中间体式II化合物；
使式II化合物脱保护得到产物；
式I的合成是以GS-441524为起始原料，在对甲苯磺酸催化下，以2,2-二甲氧基丙烷为反应试剂，选择性地在核糖2’,3’位进行保护得到中间体1，具体合成路线如下：
GS-441524、对甲苯磺酸、2,2-二甲氧基丙烷的摩尔比为1：(1～2)：(3～8)；反应的溶剂为用二氯甲烷。
中间体1和非甾体抗炎药在缩合剂DIC/DMAP作用下，选择性地在核糖5’位OH发生缩合反应得到中间体式II，具体合成路线如下：
中间体1、非甾体抗炎药、DIC、DMAP的摩尔比为1：(1～2)：(1～2)：(0.05～0.5)；反应的溶剂为用乙腈。
式II最后在甲酸水溶液中脱去丙酮叉保护得到目标化合物式I，具体合成路线如下：
本发明二联体化合物或其药学上可接受的盐或前药，可以用于制备抗冠状病毒药物。
抗冠状病毒药物是指可以用于预防、缓解和/或治疗冠状病毒感染，或其同源变异病毒的复制或繁殖及其所产生的细胞病变效应的药物。
感染包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
进一步地，所述冠状病毒包括：MHV-A59、HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV，MERS-CoV、SARS-CoV-2、小鼠肝炎病毒、猫传染性腹膜炎病毒、犬冠状病毒、牛冠状病毒、禽传染性支气管炎病毒、猪传染性胃肠炎病毒中的任意一种。
SARS-CoV-2包括SARS-CoV-2的突变株或未突变株；优选地，所述SARS-CoV-2的突变株包括SARS-CoV-2突变株B.1、SARS-CoV-2突变株B.1.351、SARS-CoV-2突变株B.1.617.2、SARS-CoV-2突变株C.37、SARS-CoV-2突变株P.1族谱、SARS-CoV-2突变株B.1.525、SARS-CoV-2突变株B.1.427或SARS-CoV-2突变株B.1.429。
一种抗冠状病毒药物，其包含作为活性成分的二联体化合物或其药学上可接受的盐或前药，和药学上可接受的载体或辅料，以用于向患者给药。
二联体化合物或其药学上可接受的盐或前药适用于人或动物；所述动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物、鸟类动物或鱼类动物。
药学上可接受的载体指用于治疗剂给药的载体，包括各种赋形剂和稀释剂。该术语指这样一些药剂载体：它们本身并不是必要的活性成分，且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的。药学上可接受的辅料是指药物中辅助性的物质，如填充剂、润滑剂、助流剂、润湿剂或乳化剂、pH缓冲物质等。
本发明所述化合物用常规载体和赋形剂配制，它们将按照常规实践进行选择。尽管能够将活性成分单独施用，但是优选将它们制成药物制剂。本发明的制剂，无论是用于兽类还是人类应用，均包含至少一种如上定义的活性成分与用于其的一种或多种可接受的载体，且任选包含其它治疗成分，尤其是如本文公开的那些另外的治疗成分。载体必须是可接受的，其含义是与制剂中的其它组分相容，并且在生理上对其接受者而言无害。
进一步地，抗冠状病毒药物为片剂、丸剂、霜剂、乳剂、软膏剂、混悬剂、冻干剂、胶囊、缓释剂、颗粒剂、冲剂、注射药剂或喷剂。
一种药物组合物，包括上述的抗冠状病毒药物，以及一种或多种其他的抗病毒药物，两种药物一起使用以提供联合治疗，其它药物可以形成相同组合物的一部分，或者可以作为同时或不同时给药的分开的组合物提供。
其他的抗病毒药物包括瑞德西韦、奥司他韦、阿比多尔、洛匹那韦、利托那韦、利巴韦林、IFN、奈玛特韦、阿兹夫定。
基于复杂难治性疾病多靶点治疗优于单药给药治疗效果更佳的特点，发明人使用孪药方法，通过酯键共价连接GS-441524的5'-OH和NSAIDs(如非诺洛芬、萘普生、酮洛芬、布洛芬、双氯芬酸和吲哚美辛等)的羧基，得到新型口服核苷类化合物ATV038～ATV043。除了直接的抗病毒作用外，这种二联体药物还能产生解热镇痛作用，以缓解症状，预防与严重感染相关的全身性炎症。此外，通过屏蔽NSAIDs的羧基，与口服NSAIDs相关的胃肠道刺激的副作用可能会得到缓解。本发明的二联体化合物对多种动物冠状病毒具有抑制作用和抗病毒效力，包括鼠冠状病毒-小鼠肝炎病毒A-59(MHV-A59)、犬冠状病毒CCoV、猫传染性腹膜炎病毒FIPV和猪传染性胃肠炎病毒TGEV，其中化合物ATV041表现出优于GS-441524的抑制活性，在较高浓度时，二联体化合物比GS-441524对体内病毒的抑制能力更强；对于β-冠状病毒MHV模型，本发明的二联体化合物可以显著抑制病毒复制，显著降低促炎介质的产生，并减少病毒引起的肝和肺组织损伤。
本发明的化合物存在两个主要的单元：GS-441524抗病毒部分和NSAIDs解热镇痛作用部分，二者通过酯键相连，使得到的二联体化合物同时具有抗病毒活性和体内抗炎症因子的作用，并达到解热镇痛疗效。同时由于疏水的非甾体抗炎药物降低了GS-441524亲水性，改善了化合物的细胞渗透性及药代动力学性质，相比GS-441524单次给药具有更高的生物利用度。
附图说明
图1是实施例10单次口服ATV041或GS-441524后1小时BALB/c小鼠体内化合物的组织分布，a：口服ATV041(200mg/kg)后GS-4415124和布洛芬在肝、肺、肾和血浆中的浓度，b：口服GS-441524(200mg/kg)后GS-4415124的浓度；每组n＝5，误差条表示SEM；
图2是实施例11在给药后3天(3dpi)，qRT-PCR检测小鼠肺和肝脏中MHV-A59 M基因拷贝丰度的结果；
图3是实施例11在3dpi时，小鼠肺和肝匀浆上清液中促炎细胞因子的检测结果；
图4、5是实施例11在3dpi时，小鼠中分离的肺和肝的代表性H&E图；
图6是实施例11肝组织血清中ALT和AST的浓度柱形图。
具体实施方式
下面结合实施例对本发明作进一步详细说明，本发明所使用的试剂均可以从市场上购得(分析纯)或者可以通过本发明所描述的方法制备而得。化合物结构确定所用的核磁共振数据由BrukerARX-400和Bruker ARX-600核磁共振仪测定，内标为TMS；高分辨质谱(HRMS)在ESI模式下用Agilent Accurate-Mass Q-TOF 6530(Agilent,Santa Clara,CA,USA)测定；纯度采用Hewlett Packard Model HP 1100高效液相色谱仪测定。
在描述实验细节时，使用了某些缩写和缩略词，DIC指N,N′-二异丙基碳二亚胺，ACN指乙腈，DCM指二氯甲烷，DMAP指4-二甲氨基吡啶，EA指乙酸乙酯，MeOH指甲醇，PE指石油醚，rt指室温，THF指四氢呋喃，TLC指薄层色谱法，FA指甲酸，μM表示微摩尔每升；mmol表示毫摩尔；equiv表示当量。
实施例1
化合物1的合成
向100mL单口瓶中加入GS-441524(10.0g,0.034mol)、对甲苯磺酸(5.8g，0.034mol)、2,2-二甲氧基丙烷(22g，0.21mmol)，用二氯甲烷(50mL)溶解。在室温下搅拌，室温反应8h后，TLC监测原料完全消耗。用正庚烷(100mL)稀释反应液，再搅拌2小时，产生大量白色固体，固体抽滤，滤饼用饱和碳酸钠溶液洗涤。于50℃下真空干燥，得到白色固体中间体1(10.7g，产率为95％)。
1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.08(d,J＝4.6Hz,1H),6.66(d,J＝4.9Hz,1H),5.98(s,2H),5.43(d,J＝6.5Hz,1H),5.24(dd,J＝6.6,2.3Hz,1H),4.67(q,J＝1.9Hz,1H),4.04–3.74(m,2H),1.81(s,3H),1.40(s,3H)。
实施例2
化合物ATV038的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、非诺洛芬(0.73g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品经过柱层析分离(洗脱液为：石油醚/乙酸乙酯(V/V)＝1/1)，得到白色固体2(1.5g,产率为90％)，ESI-MS:m/z 556.1[M+H]+。
将1.50g的化合物2溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到白色固体ATV038(0.74g,产率为53％)。
HPLC纯度:>99％；1H NMR(600MHz,DMSO-d6)δ7.94(br,2H),7.90(s,1H),7.45–
7.24(m,3H),7.18–6.81(m,7H),6.71(dd,J＝38.9,4.5Hz,1H),6.33(dd,J＝26.5,6.0Hz,1H),5.45–5.30(m,1H),4.67–4.53(m,1H),4.40–4.10(m,3H),3.97–3.70(m,2H),3.35(s,3H),1.41–1.27(m,3H)；13C NMR(151MHz,DMSO-d6)δ173.9,173.8,157.3,157.2,156.8,156.0,148.4,143.1,143.0,130.6,130.5,130.5,124.0,123.9,123.9,123.0,122.7,119.2,119.1,118.1,117.9,117.5,117.4,117.0,110.6,101.4,101.3,81.7,81.4,79.6,79.4,74.5,70.5,65.4,64.1,63.8,44.7,19.0,18.8；ESI-HRMS:m/z[M+H]+calcd forC27H26N5O6:516.1883；found:516.1876。
实施例3
化合物ATV039的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、萘普生(0.69g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品未经纯化，直接用于下一步反应。
将上述化合物3粗品溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到0.77g化合物ATV039(白色固体，两步产率为52％)。
HPLC纯度:99.88％；1H NMR(600MHz,DMSO-d6)δ7.96(br,2H),7.92(s,1H),7.74–7.68(m,2H),7.65(s,1H),7.33(dd,J＝8.5,1.8Hz,1H),7.26(d,J＝2.5Hz,1H),7.12(dd,J＝9.0,2.5Hz,1H),6.93(d,J＝4.5Hz,1H),6.75(d,J＝4.5Hz,1H),6.24(d,J＝6.1Hz,1H),5.34(d,J＝5.8Hz,1H),4.59(t,J＝5.5Hz,1H),4.37(dd,J＝12.1,2.6Hz,1H),4.25–4.14(m,2H),3.90–3.86(m,2H),3.86(s,3H),1.43(d,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO-d6)δ173.7,157.2,155.6,147.9,135.4,133.3,129.1,128.3,127.0,126.1,125.6,123.5,118.7,116.9,116.6,110.3,105.7,100.9,81.4,78.9,74.0,70.0,63.3,55.2,44.4,18.4；ESI-HRMS:m/z[M+H]+calcd for C26H26N5O6:504.1883；found:504.1876。
实施例4
化合物ATV040的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、酮洛芬(0.76g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品未经纯化，直接用于下一步反应。
将上述化合物4粗品溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到0.81g化合物ATV040(白色固体，两步产率为51％)。
HPLC纯度:>99％；1H NMR(600MHz,DMSO-d6)δ7.95(br,2H),7.91(s,1H),7.73–
7.42(m,9H),6.88(dd,J＝9.1,4.5Hz,1H),6.69(dd,J＝42.0,4.5Hz,1H),6.32(dd,J＝28.4,6.1Hz,1H),5.39(dd,J＝11.5,5.9Hz,1H),4.59(dt,J＝23.5,5.5Hz,1H),4.43–4.14(m,3H),4.00–3.78(m,2H),1.45–1.34(m,3H)；13C NMR(151MHz,DMSO-d6)δ196.0,173.9,156.0,148.4,141.3,137.7,137.6,137.3,133.2,133.1,132.4,132.1,130.1,130.0,129.3,129.3,129.0,129.0,128.9,123.9,117.3,117.0,117.0,110.6,110.6,101.4,101.3,81.7,81.5,79.5,79.4,74.5,74.5,70.5,70.5,64.2,63.9,55.4,44.6,19.0,18.9；ESI-HRMS:m/z[M+H]+calcd for C28H26N5O6:528.1883；found:528.1877。
实施例5
化合物ATV041的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、布洛芬(0.62g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品未经纯化，直接用于下一步反应。
将上述化合物5粗品溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到0.83g化合物ATV041(白色固体，两步产率为56％)。
HPLC纯度:>99％；1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝1.7Hz,6H),7.18–7.13
(m,2H),7.12–7.06(m,4H),7.01(d,J＝8.0Hz,2H),6.93(dd,J＝5.6,4.5Hz,2H),6.75(d,J＝4.5Hz,1H),6.67(d,J＝4.5Hz,1H),6.35–6.23(m,2H),5.39–5.25(m,2H),4.69–4.52(m,2H),4.37–4.31(m,1H),4.28–4.13(m,5H),3.96–3.88(m,1H),3.86–3.79(m,1H),3.77–3.67(m,2H),2.41(d,J＝7.2Hz,2H),2.36(d,J＝7.1,1.8Hz,2H),1.85–1.64(m,2H),1.42–1.26(m,6H),0.88–0.69(m,12H)；13C NMR(151MHz,DMSO)δ174.3,174.2,156.1,156.1,148.4,148.4,140.3,140.2,138.1,129.6,129.5,127.5,127.5,124.0,117.4,117.3,117.0,117.0,110.7,110.7,101.4,101.4,81.8,81.4,79.5,79.4,74.5,70.4,70.4,63.8,63.5,44.7,44.7,44.6,44.5,30.0,30.0,23.8,22.7,22.6,22.5,19.1,18.9；ESI-HRMS:m/z[M+H]+calcd for C25H30N5O5:480.2247；found:480.2241。
实施例6
化合物ATV042的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、双氯芬酸(0.89g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品未经纯化，直接用于下一步反应。
将上述化合物6粗品溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到0.82g化合物ATV039(白色固体，两步产率为47％)。
HPLC purity:>99％；1H NMR(600MHz,DMSO-d6)δ7.97(br,2H),7.94(s,3H),7.52(d,J
＝8.1Hz,2H),7.21(t,J＝8.1Hz,1H),7.15(dd,J＝7.5,1.6Hz,1H),7.10–7.01(m,2H),6.92(d,J＝4.5Hz,1H),6.86–6.76(m,2H),6.34(d,J＝6.0Hz,1H),6.24(dd,J＝8.1,1.2Hz,1H),5.42(d,J＝5.9Hz,1H),4.67(dd,J＝6.0,4.9Hz,1H),4.40(dd,J＝11.8,2.4Hz,1H),4.32–4.19(m,2H),3.82(s,2H)；13C NMR(151MHz,DMSO-d6)δ171.9,156.1,148.4,143.4,137.5,131.4,131.3,129.6,128.3,126.5,123.9,123.3,121.0,117.4,117.0,116.2,110.8,101.4,81.6,79.7,74.4,70.7,64.5,37.3；HPLC purity:％.ESI-HRMS:m/z[M+H]+calcd for C26H23Cl2N6O5:569.1107；found:569.1101。
实施例7
化合物ATV043的合成
向50mL单口瓶中加入中间体1(1.0g,3.0mmol)、吲哚美辛(1.1g,3.0mmol)、DMAP(36.6mg，0.3mmol)，用ACN(20mL)溶解。再于冰水浴下，滴加DIC(0.62g，3.2mmol)的ACN(5mL)溶液。反应液在室温下搅拌12小时后，过滤去除不溶固体，滤液用30mL柠檬酸水溶液(20％w/v)洗涤、再用30mL饱和碳酸钠溶液洗涤。用无水硫酸钠干燥。抽滤蒸干，粗品未经纯化，直接用于下一步反应。
将上述化合物6粗品溶于10mL(6.7V)甲酸和5mL(3.3V)水中，于室温下搅拌30小时后，蒸干多余的甲酸，剩余物用乙酸乙酯溶解后，用饱和碳酸钠水溶液调节pH至8，分出有机层，水层用EA萃取两次后，合并有机层，用饱和食盐水洗涤后，硫酸钠干燥，抽滤蒸干，粗品经过柱层析分离(洗脱液为：DCM/MeOH(V/V)＝10/1)，得到0.71g化合物ATV039(白色固体，两步产率为0.37％)。
HPLC纯度:99.76％；1H NMR(600MHz,DMSO-d6)δ7.93(s,3H),7.70–7.58(m,4H),6.98(d,J＝2.5Hz,1H),6.94(d,J＝9.0Hz,1H),6.90(d,J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),6.71(dd,J＝9.0,2.6Hz,1H),6.31(d,J＝6.0Hz,1H),5.41(d,J＝5.8Hz,1H),4.69–4.61(m,1H),4.43–4.32(m,1H),4.30–4.21(m,2H),3.95(q,J＝5.8Hz,1H),3.79(s,2H),3.71(s,3H),2.18(s,3H)；13C NMR(151MHz,DMSO)δ174.3,174.2,156.1,156.1,148.4,148.4,140.3,140.2,138.1,129.6,129.5,127.5,127.5,124.0,117.4,117.3,117.0,117.0,110.7,110.7,101.4,101.4,81.8,81.4,79.5,79.4,74.5,70.4,70.4,63.8,63.5,44.7,44.7,44.6,44.5,30.0,30.0,23.8,22.7,22.6,22.5,19.1,18.9；ESI-HRMS:m/z[M+H]+calcd for C31H28ClN6O7:631.1708；found:631.1701。
实施例8
二联体化合物体外抗MHV-A59、CCoV、FIPV和TGEV活性测定
分别在含有L929细胞、CRFK细胞和ST细胞的培养基中加入10％FBS、100U/mL青霉素和链霉素的DMEM，将细胞保存在37℃、5wt％CO2环境下培养。用MHV-A59(0.01MOI)感染L929细胞，用CCoV和FIPV(0.01MOi)感染CRFK细胞，用TGEV(0.01MoI)在37℃下感染ST细胞1h。DMSO作为空白对照。在37℃孵育48小时后，收集细胞和上清液，通过qRT-PCR测定病毒载量。基于病毒拷贝数计算类似物的抑制率，并使用Graphpad Prism软件8.0计算50％有效浓度(EC50)。
qRT-PCR测定：用TRIzol试剂从细胞或组织样品中分离总RNA。通过PrimeScriptRT试剂盒(Takara)将mRNA逆转录成cDNA。使用ChamQ Universal SYBR qPCR Master Mix(Vazyme Biotech Co.，Ltd)或Taq Pro HS Universal Probe Master Mix(VazimeBiotechy Co.，Ltd)，通过快速两步扩增程序扩增cDNA。GAPDH用于通过ΔCt方法对输入样本进行归一化。将每个基因的相对mRNA表达水平归一化为未处理条件下的GAPDH管家基因表达，并通过ΔΔCT法计算相对于未处理样品的折叠诱导。
结果见表1(—表示未进行测试)。结果显示，实施例2～7合成的二联体化合物对冠状病毒MHV-59都具有与阳性化合物GS-441524相当或更佳的抑制活性，尤其是化合物ATV041抑制MHV的EC50值为1.15μM。化合物ATV041对多种动物冠状病毒都表现出优于GS-441524的抑制活性，有望发展成为一种广谱的抗冠状病毒药物。
表1.二联体化合物对抗MHV-A59、CCoV、FIPV和TGEV的体外活性
实施例9
化合物ATV041的药代动力学研究
雄性SD大鼠(n＝3)在给药前禁食12小时，ATV041以5mg/kg静脉给药或以25mg/kg胃内给药。静脉注射组分别在0.083、0.25、0.5、1、2、3、4、6、8和24小时，口服组分别在0.25、1、0.5、2、4、4、8和24h将血样从颈静脉采集到抗凝EDTA-K2管中。所有样品在4℃下以4000rpm/min的速度离心10分钟，收集血浆(上清液)并在-65℃下储存以备将来分析，用250μL乙腈处理50μL血浆样品的等分试样，将样品在4000rpm/min下离心10分钟，并通过0.2μm膜过滤器过滤，通过LC/MS/MS分析每个样品中分析物的浓度。报告了以下PK参数：清除率(CL；L/h/kg)、稳态分布体积(Vss；L/kg)、终末半衰期(T1/2；h)、最大浓度(Cmax；μM)和浓度下面积-从时间0到无穷大的时间曲线(AUCinf；μM·h)。
结果如表2所示。结果显示，ATV041体内水解产生的GS-441524显示出60.3％的高口服生物利用度(F％)和4.98小时的半衰期(T1/2)。口服给药后0.7小时，Cmax达到7.75±1.58μM/L，表明其高于有效浓度的血液暴露。与GS-441524单次给药的不良口服PK相比，二联体ATV041改善了GS-4415124的口服暴露。此外，口服ATV041导致布洛芬的高口服暴露，生物利用度为78％。
表2.SD大鼠单剂量给药ATV041后的PK参数a
aSD大鼠单次口服(25mg/kg)或单次静脉注射(5mg/kg)ATV041后以GS-441524和布洛芬的PK参数计算。结果显示为平均值±标准差(SD)，n＝3。
实施例10
ATV041组织分布评价
10只雄性BALB/c小鼠随机分为两组。所有大鼠均以单剂量200mg/kg ATV041(n＝5)或200mg/kg GS-441524(n＝6)进行胃内给药。给药后1小时，麻醉小鼠，采集包括肾、肝、肺和血浆在内的组织，采集血样并离心以获得血浆。所有样品均在-80℃下储存以备进一步使用，将组织样品单独均质化，通过LC-MS/MS分析血浆和组织匀浆中关键代谢物GS-441524和布洛芬的浓度。
结果见图1所示。结果表明，ATV041水解后的GS-441524和布洛芬在小鼠组织中分布广泛且迅速(图1a，左列为GS-441524浓度，右列为布洛芬浓度)。值得注意的是，尽管布洛芬的血浆浓度比GS-441524高10倍，但它们在组织中的差异不如血浆中的显著。相反，在所有样品中，GS-441524口服给药小鼠的GS-4415124浓度(图1b)比口服ATV041低约5倍。
实施例11
ATV041在BALB/c小鼠体内抗MHV活性评价
将无特定病原体(SPF)雄性BALB/c小鼠(3至4周)用异氟烷通过呼吸麻醉，并接受30μL MHV-A59(TCID50＝10-7.125/100μL)磷酸盐缓冲盐水(PBS)鼻内接种。然后将感染小鼠随机分为7组(A组，B1～B3，C1～C3)：空白(MHV小鼠，A组)、GS-441524(100mg/kg，QD，B1组)、布洛芬(70mg/kg，QD，B2组)、布洛芬(70mg/kg，QD)加上GS-4415124(100mg/kg，B3组)、ATV041(10mg/kg，C1组)、ATV041(50mg/kg，C2组)、ATV041(200mg/kg，C3组)，每组12只动物。将药物溶解在溶媒中(15％ Cremophor EL,82.5％ PBS和2.5％DMSO)。在感染病毒的1小时候开始口服给药，持续4天。用溶媒处理正常小鼠(D组)。每天监测小鼠的疾病症状：包括体重、临床症状和死亡，持续23天。每组4只小鼠在第3天处死，收集肺和肝组织进行qRT-PCR检测、促炎细胞因子检测和组织病理学检查，并取血浆进行AST(谷草转氨酶)和ALT(谷丙转氨酶)分析。
qRT-PCR检测结果如图2所示，肺和肝匀浆中的qPCR分析显示，病毒RNA拷贝在3dpi时在肝和肺中均达到高水平。在相同摩尔浓度(34mM/kg)下，GS-441524(B1)、GS-4415124与布洛芬(B3)、200mg/kg的ATV041(C3)显著抑制了肝脏中的病毒复制，使其低于检测限。相比之下，低剂量10mg/kg(C1)和中剂量50mg/kg(C2)的ATV041表现出剂量依赖性地抑制病毒RNA拷贝的趋势。单独服用布洛芬(B2)没有显示出抗病毒效果。另一方面，药物在肺部的抗病毒效力不如在肝脏的效力，尽管如此，200mg/kg的ATV041(C3)显著抑制了肺部的病毒复制，使其低于检测限。GS-441524(B1)单独抑制病毒复制约一个数量级；GS-441524和布洛芬的组合(B3)将病毒mRNA抑制了五个数量级，显示出显著的协同效应。ATV041表现出对病毒复制的剂量依赖性抑制，200mg/kg ATV041(C3)抑制病毒至低于检测限，在相同摩尔浓度下比GS-441524更有效。
促炎细胞因子检测结果如图3所示，结果表明，在肝脏中，ATV041显著降低了关键促炎介质的产生，如TNF-α、IL-1β、IL-6、IFN-γ和CXCL10。由于抑制了病毒在组织中的复制，抗病毒细胞因子IFN-β也显著降低。布洛芬单独对这里测试的炎症介质没有明显影响。肺中的抗炎作用不如肝中的那么明显，ATV041比单独的GS-441524和GS-4415124加布洛芬更有效。值得注意的是，在200mg/kg的高剂量下，促炎因子显著降低到与正常小鼠相似的水平。
组织病理学检查结果如图4、5所示，图4是肺部，图5是肝部，MHV感染小鼠肺切片存在中度间质性肺炎伴肺泡间隔增厚、淋巴细胞浸润和坏死碎片，而ATV041给药小鼠在3dpi时肺症状减轻。ATV041具有与GS-441524相似的明显缓解效果。
血清AST和ALT的分析结果如图6所示，ATV0041治疗显著降低了血浆丙氨酸氨基转移酶和天冬氨酸氨基转移酶的浓度，表明MHV-A549引起的急性肝损伤得到缓解。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。
Claims (9)
1.一种非甾体抗炎药和GS-441524的二联体化合物或其药学上可接受的盐，结构如下：化合物ATV038
化合物ATV039
化合物ATV040
化合物ATV041
化合物ATV042
2.根据权利要求1所述的二联体化合物或其药学上可接受的盐，其结构为：
化合物ATV041
3.根据权利要求1或2所述的二联体化合物或其药学上可接受的盐，包括其外消旋体。
4.根据权利要求1或2所述的二联体化合物或其药学上可接受的盐的制备方法，其特征在于，包括以下步骤：
使GS-441524和2,2-二甲氧基丙烷反应得到中间体1；
使中间体1与非甾体抗炎药NSAID反应得到中间体式II化合物；
使式II化合物脱保护得到产物；
所述非甾体抗炎药NSAID为非诺洛芬、萘普生、酮洛芬、布洛芬或双氯芬酸；
5.权利要求1所述的二联体化合物或其药学上可接受的盐在制备抗冠状病毒药物中的用途，所述冠状病毒为MHV-A59。
6.权利要求2所述的二联体化合物或其药学上可接受的盐在制备抗冠状病毒药物中的用途，所述冠状病毒为小鼠肝炎病毒、猫传染性腹膜炎病毒、犬冠状病毒、牛冠状病毒、禽传染性支气管炎病毒或猪传染性胃肠炎病毒。
7.一种抗冠状病毒药物，其包含作为活性成分的一种或多种如权利要求1或2所述的二联体化合物或其药学上可接受的盐，和药学上可接受的载体或辅料。
8.根据权利要求7所述的抗冠状病毒药物，其为片剂、丸剂、霜剂、乳剂、软膏剂、混悬剂、冻干剂、胶囊、缓释剂、颗粒剂、冲剂、注射药剂或喷剂。
9.一种药物组合物，包括权利要求7或8的抗冠状病毒药物，以及一种或多种其他的抗病毒药物。
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